4-(4-Fluorophenyl)-N-alkylnipecotinate esters of general formula A represent key intermediates in the synthesis of 4-arylpiperidine-based compounds. It is noteworthy that 4-arylpiperidine is an important structural motif in many biologically active compounds (M. Engelstoft and J. B. Hansen, Acta Chemical Scandinavica, 50, 1996, pp. 164–169).

An example is (−)-menthyl (3S,4R)-trans-4-(4-fluorophenyl)-N-methylnipecotinate hydrobromide (1) which is a key intermediate in the synthesis of paroxetine. Paroxetine (Paxil®) is a highly effective chiral pharmaceutical that is useful for the treatment of depression and obsessive compulsive disorder.

The use of this compound for this purpose was disclosed in U.S. Pat. Nos. 3,912,743 and 4,007,196 whereby 4-fluorophenylmagnesium bromide was added to arecoline. The resulting adduct was epimerized and the methyl ester functionality hydrolyzed, activated using thionyl chloride, esterified using (−)-menthol, and salt formation using hydrobromic acid to provide compound 1, as depicted in Scheme 1, which was further elaborated to paroxetine using standard procedures.

The procedure disclosed in these patents for the key Grignard conjugate addition step was based on a procedure developed by Plati et al. (U.S. Pat. No. 2,546,652 and Journal of Organic Chemistry, 22, 1957, pp. 261–265) for the reaction of phenylmagnesium bromide in diethyl ether with arecoline, also in diethyl ether. Thus, a major deficiency of this process, and likewise the processes disclosed in U.S. Pat. Nos. 3,912,743 and 4,007,196, was the diethyl ether in both the arylmagnesium bromide reagent and the reaction media. Diethyl ether is a highly flammable solvent which is undesirable to use industrially. According to patents by Ward [(U.S. Pat. No. 6,172,233) and Ward et al. (WO 01/17966A1 and WO 01/29032A1)], the use of other ether solvents conventionally used in Grignard reactions, such as tetrahydrofuran (THF) or diisopropyl ether, furnished little, if any, of the desired 1,4-conjugate addition product, with the main by-product arising from 1,2-addition of the Grignard reagent on the ester grouping. From an industrial perspective, a multistep transformation in which one step resulted in, “little if any of the desired product” (for instance <10% yield) would be prohibitively expensive. Compounding this deficiency, if this process were to be used for the synthesis of paroxetine, is the fact that the low yielding step occurs at a rather late-stage in the paroxetine process, thereby necessitating the processing of large volumes of intermediary products in order to reach the Grignard reaction step. Also, disclosed in the Ward patent was the observation that when performing the reaction using the process described by Plati et al., the reaction mixture purportedly generated thick unstirrable gels.
These deficiencies were purportedly overcome by Ward by the use of a reaction solvent mixture which was non-wholly ether, as utilized by Plati et al. As well, the Ward patents purport that the use of organometallic compounds in place of the Grignard reagent also overcame these deficiencies. However, in all examples in the Ward patents, the Grignard reagent used was always a 2M solution of 4-fluorophenylmagnesium bromide in diethyl ether. Specifically, in examples 2, 3, 4 and 5 of U.S. Pat. No. 6,172,233, the weight percentage of diethyl ether introduced by the 4-fluorophenylmagnesium bromide in diethyl ether reagent relative to the total reaction volume was about 23 to 31% range. Therefore the disadvantage of having a process which necessitated diethyl ether, with all of the disadvantages associated with this solvent, largely remained. In example 1 of the same patent, the diethyl ether is removed from the 2M 4-fluorophenylmagnesium bromide reagent prior to the addition to arecoline by co-distillation with toluene. However, this requires an extra process operation and, again, does not avoid the use of diethyl ether on an industrial scale.
Similar reactions have also been utilized for transformations of this type. For instance, Murthy and Rey in U.S. Pat. No. 5,962,689 disclose the stereoselective addition of 4-fluorophenylmagnesium bromide to various 3,4-unsaturated-3-piperidine esters, amides and N-enoylsultams in toluene. Xu and Trudell (J. Heterocyclic Chem., 33, 1996, pp. 2037–2039) also described the addition of various arylmagnesium bromide reagents, including 4-fluorophenylmagnesium bromide, to R-(−)-anhydroecgonine methyl ester substrates in dichloromethane. The disadvantage in both of these publications is that a solution of the aryl Grignard reagent in diethyl ether was employed.
It is therefore an object of the invention to provide a process which utilizes solvents other than diethyl ether to arrive at yields greater than “little if any” of the desired product.
It is therefore also another object of the invention to provide a process that is easy to perform and incorporates solvents that are less flammable and/or less toxic relative to solvents used as reaction media in the prior art.
It is also an object of the invention to provide a process which results in substantially no gels being formed, even on scale up to industrial quantities.
Further and other objects of the invention will become apparent to a person reading the following.